Diabetes has reached epidemic proportions. Approximately 15 million people in the United States are currently afflicted with the disease, and that number is expected to rise to at least 21 million over the next 30 years.
In addition to (and as a consequence of) the metabolic disarray caused by the disease, diabetes causes a variety of other, organ-specific dysfunctions, including in particular diabetic retinopathy. Diabetic retinopathy affects half of all Americans diagnosed with diabetes. Diabetic retinopathy is an illness that occurs when diabetes damages tiny blood vessels in the retina, affecting vision, and is a leading cause of blindness. There are two clinical stages of retinopathy. The first stage is known as nonproliferative retinopathy, in which the blood vessels damaged by diabetes leak fluid and lipids onto the retina. When the fluid accumulates in the center of the retina (i.e., the macula) it leads to macular edema. The fluid makes the macula swell, which blurs vision. The second stage is the proliferative stage, where new blood vessels grow along the retina and in the clear, gel-like vitreous that fills the inside of the eye. These new blood vessels can bleed, cloud vision, and destroy the retina unless treated. There is also a preclinical phase in which patients will generally have no symptoms, nor will there be any findings on routine clinical examination. However, in the preclinical phase sensitive tests reveal reduced contrast sensitivity, electrical responses with an electroretinogram, or color vision.
There are several methods of treatment for diabetic retinopathy disclosed in the art. However, none of these treatment approaches have proven successful in addressing the primary metabolic disorder or in preventing retinopathy. Conventional diabetic retinopathy treatments are limited to controlling the diabetic state with systemic insulin administration or oral hypoglycemic agents. The problem with these systemic approaches is that they do not restore normal physiologic metabolic control or provide overall effective levels of the drug to the eye. Secondary treatment approaches include using diuretics to control blood pressure or intravascular fluid overload. Attempts have also been recognized in the arts for treating retinopathy with aldose reductase inhibitors, inhibitors of nonenzymatic glycation (aminoguanidine), corticosteroids or antihistamines. Methods of treatment for advanced retinopathy complications include vitrectomy surgery and laser treatment, exposing an intense beam of light to the small diseased areas of the retina. These methods are palliative in nature, and none of these methods is sufficiently effective to prevent or cure the disease.
Although diabetic retinopathy is extensively studied in the art, the direct effects of insulin or insulinomimetics on diabetic retinopathy are limited. It has been demonstrated that retinal neurons die in experimental diabetes in rats and in humans. Moreover, insulin has been shown to be a survival factor for retinal neurons in culture, and excess hexosamines impair insulin's survival-promoting effects. In vivo, systemically and intraocularly administered insulin activates the insulin receptor and downstream signaling cascades that are involved in cell function and survival. However, the ability to administer systemically sufficient insulin or other insulinomimetic agents to be effective for prevention of retinopathy is limited by the risk of hypoglycemia.
Accordingly, there is a great demand for safe and effective methods for delivering agents effective in treating diabetic retinopathy. In particular, there is a need in the art for treatment methods that maintain retinal cell function and survival in the face of persistent hyperglycemia.